Enhancement of bismuth antibacterial activity with lipophilic thiol chelators

Abstract

The antibacterial properties of bismuth are greatly enhanced when bismuth is combined with certain lipophilic thiol compounds. Antibacterial activity was enhanced from 25- to 300-fold by the following seven different thiols, in order of decreasing synergy: 1,3-propanedithiol, dimercaprol (BAL), dithiothreitol, 3-mercapto-2-butanol, beta-mercaptoethanol, 1-monothioglycerol, and mercaptoethylamine. The dithiols produced the greatest synergy with bismuth at optimum bismuth-thiol molar ratios of from 3:1 to 1:1. The monothiols were generally not as synergistic and required molar ratios of from 1:1 to 1:4 for optimum antibacterial activity. The most-active mono- or dithiols were also the most soluble in butanol. The intensity of the yellow formed by bismuth-thiol complexes reflected the degree of chelation and correlated with antibacterial potency at high molar ratios. The bismuth-BAL compound (BisBAL) was active against most bacteria, as assessed by broth dilution, agar diffusion, and agar dilution analyses. Staphylococci (MIC, 5 to 7 microM Bi3+) and Helicobacter pylori (MIC, 2.2 microM) were among the most sensitive bacteria. Gram-negative bacteria were sensitive (MIC, < 17 microM). Enterococci were relatively resistant (MIC, 63 microM Bi3+). The MIC range for anaerobes was 15 to 100 microM Bi3+, except for Clostridium difficile (MIC, 7.5 microM). Bactericidal activity averaged 29% above the MIC. Bactericidal activity increased with increasing pH and/or increasing temperature. Bismuth-thiol solubility, stability, and antibacterial activity depended on pH and the bismuth-thiol molar ratio. BisBAL was stable but ineffective against Escherichia coli at pH 4. Activity and instability (reactivity) increased with increasing alkalinity. BisBAL was acid soluble at a molar ratio of greater than 3:2 and alkaline soluble at a molar ratio of less than 2:3. In conclusion, certain lipophilic thiol compounds enhanced bismuth antibacterial activity against a broad spectrum of bacteria. The activity, solubility, and stability of BisBAL were strongly dependent on the pH, temperature, and molar ratio. Chelation of bismuth with certain thiol agents enhanced the solubility and lipophilicity of this cationic heavy metal, thereby significantly enhancing its potency and versatility as an antibacterial agent.

Syntheses, crystal structures and antimicrobial activities of monomeric 8-coordinate, and dimeric and monomeric 7-coordinate bismuth(III) complexes with tridentate and pentadentate thiosemicarbazones and pentadentate semicarbazone ligands

“…In general, bismuth(III) complexes with multidentate thiosemicarbazone and semicarbazone ligands have shown selective activities against bacteria, but not yeasts and molds, whereas the antimony(III) complexes with the same ligands have shown the lower levels of activities, although the latter complexes have shown a wider spectrum of antimicrobial activities, i.e., they showed also the activities against yeasts and molds [43]. These facts are consistent with the previously reported data [44].…”

Antifungal activity of organobismuth compounds against the yeast Saccharomyces cerevisiae: structure–activity relationship

“…In particular, bismuth salts such as colloidal bismuth subcitrate (CBS), bismuth subsalicylate (BSS) and ranitidine bismuth citrate (RBC) are now common agents for such purpose [8]. The recent demonstration that these salts are useful for Helicobacter pylori eradication therapy [8,9] has promoted antibacterial [10][11][12][13][14][15][16][17][18] or antitumor [19] studies of various bismuth compounds, and some of the biologically active derivatives have been characterized by X-ray structure analysis. Despite the long history of the use of bismuth as medicinal agents, however, the mechanism of the biological action of bismuth is not fully understood [1,8,9,18].…”

Inhibition of Bacterial Adherence on the Surface of Stents and Bacterial Growth in Bile by Bismuth Dimercaprol

“…diarrhea and for the eradication of Helicobacter pylori in the stomach (8)(9)(10)(11)(12). Recently, the antibacterial properties of bismuth have been greatly enhanced, up to 1000-fold, through combination with certain lipophilic thiol compounds, thereby significantly enhancing its potency and versatility as an antibacterial agent (13). A series of reports from Domenico et al demonstrated the unique effects of bismuth thiols compounds at low concentrations on bacterial virulent factors such as exopolysaccharide expression and bacterial biofilm formation (14)(15)(16).…”